When the Portuguese arrived in 1522, they built a port and named it São Tomé, after the Christian apostle St. Thomas, who is believed to have preached there between the years 52 and 70. The region then passed into the hands of the Dutch, who established themselves near Pulicat just north of the city in 1612.

On 22 August 1639, the British East India Company was granted land by the Damerla Venkatadri, Nayak of Vandavasi, as a base for a permanent settlement, believed to be called Madrasemen. A year later, Fort St George was built, which subsequently became the nucleus around which the colonial city grew. In 1746, Fort St George and Madras were captured by the French under General La Bourdonnais, the Governor of Mauritius, who plundered the town and its outlying villages.

The British regained control of the town in 1749 through the Treaty of Aix-la-Chapelle and subsequently fortified the base to withstand further attacks from the French and Hyder Ali, the Sultan of Mysore. By the late 18th century, the British had conquered most of the region around Tamil Nadu and the northern modern-day states of Andhra Pradesh and Karnataka to establish the Madras Presidency, whose capital was Madras.

Under British rule the city grew into a major urban centre and naval base. With the advent of railways in India in the late 19th century, it was connected to other important cities such as Mumbai (formerly known as Bombay) and Kolkata (formerly Calcutta), facilitating communication and trade with the hinterland. It was the only Indian city to be attacked by the Central Powers during World War I, when an oil depot was shelled by the German light cruiser SMS Emden. After independence in 1947, the city became the capital of Madras State, which was renamed Tamil Nadu in 1969.

From 1965 to 1967, Chennai was an important base for the Tamil agitation against the imposition of Hindi. Chennai had witnessed some political violence due to the ethnic conflict in Sri Lanka, after 33 people were killed by a bomb planted by the Tamil Eelam Army at the airport in 1984 and following the assassination of thirteen members of the Sri Lankan separatist group EPRLF, and two Indian civilians by the rival LTTE in 1991. Strong measures were taken and the city has not faced any major terrorist activity since then. The city was renamed Chennai in August 1996 as the name Madras was perceived to be of Portuguese origin.

In 2004 the Indian Ocean tsunami lashed the shores of Chennai, killing many and permanently altering the coastline.